Injectable pharmaceutical formulations

ABSTRACT

The present invention relates to a process for suppressing the foaming which may occur at the time of the preparation of a solution or a suspension. Particularly, the present invention relates to pharmaceuticals, foods, and the like wherein the foaming at the time of the preparation of a solution or a suspension, which may cause any disadvantage, is suppressed.

This application is a U.S. national stage of International ApplicationNo. PCT/JP02/07190 filed Jul. 16, 2002.

FILED OF THE INVENTION

The present invention relates to a process for suppressing the foamingwhich may occur at the time of the preparation of a solution or asuspension. Particularly, the present invention relates topharmaceuticals, foods, and the like wherein the foaming at the time ofthe preparation of a solution or a suspension, which may cause anydisadvantage, is suppressed.

BACKGROUND ART

The compound (compound 1) of formula:

is a medicament for treating acute cerebro-vascular accidents such asintracerebral hemorrhage, cerebral infarction, and subarachnoidhemorrhage, and Japanese Patent Publication (kokai) No. 53484/1995describes the same and related compounds as well as their preparations.

Compound 1 as described above is considered to be administered viaintravenous infusion. In this case, a lyophilized formulation sealedclosely in vials is first reconstituted or suspended in a water forinjection or an infusion liquid therein, and then the solution or thesuspension is mixed with an additional infusion liquid (about 100 to 500ml, pH about 6 to 7) before use. However, vigorous mixing at the time ofthe dissolution/suspension in vials may cause the foaming, which hasbeen recognized to lead to problems that it is difficult to transfer thewhole contents of an effective ingredient into an additional infusionliquid, which would bring about a margin of error in dose, and that thefoaming prevents from the reconstitution of the present compound whenthe dose is increased up to about 300 mg. Although it is possible toconduct the stirring smoothly on a table for example, such stirringwould be an unpractical means in medical applications, showing that thesuppression of foaming has been interested.

DISCLOSURE OF THE INVENTION

Under the circumstance, the inventors of the present application focusedon the dissociation constant of compound 1, and found that the foamingis suppressed by adjusting the pH with a basic agent.

Japanese Patent Publication (kokai) No. 124481/1997 describeslyophilized formulations that are readily rendered clear, which isprovided by using a vial coated with silicon as a formulation containerto prevent the attachment of the foams that occur at the time of theresolution onto the inside of the vial. However, no foam suppressionassociated with pharmaceutical products has been reported. In industrialfields other than the pharmaceutical field, foams are suppressed byaddition of silicons or alcohols, or foams are destroyed by mechanicalmeans.

Specifically, as the first aspect, the invention provides:

an injectable pharmaceutical formulation which comprises an effectiveingredient and a basic agent, wherein the effective ingredient meets therequirements:

-   -   1) it has a phenolic hydroxyl group;    -   2) its dissociation constant (pKa value) is 8 or more; and    -   3) the solution or the suspension containing the effective        ingredient at a concentration of 30 to 40 mM shows a surface        tension of 60 mN/m or less as determined by Wilhelmy method        (solvent: water, determination temperature: 25° C.), and        wherein the pH of the formulation in a state of solution or        suspension is 8.5 or more; preferably, the pharmaceutical        formulation, wherein the effective ingredient is a compound of        formula (I):

in which R¹ is a hydrogen, or a metabolizable ester residue; and R² is ahydrogen, or —R³—R⁴ wherein R³ is —SO₃—, —CH₂COO—, —COCOO— or COR⁵COO—wherein R⁵ is a C1-C6 alkylene or a C2-C6 alkenylene, and R⁴ is ahydrogen or a C1-C6 alkyl; or a pharmaceutically acceptable saltthereof, or a solvate of them; and

As the second aspect, the invention provides:

a process for suppressing the foaming that occurs when a compound havinga phenolic hydroxyl group is dissolved or suspended in an aqueoussolvent, which comprises dissociating the phenolic hydroxyl group at thetime of the dissolution or the suspension; preferably the process forsuppressing the foaming, wherein the compound meets the requirements:

-   -   1) its dissociation constant (pKa value) is 8 or more; and    -   2) the solution or the suspension containing the compound at a        concentration of 30 to 40 mM shows a surface tension of 60 mN/m        or less as determined by Wilhelmy method (solvent: water,        determination temperature: 25° C.); more preferably the process        wherein a basic agent is used to allow the dissociation, even        more preferably the process for suppressing the foaming, wherein        the basic agent renders the pH of the solution or the suspension        to be 8.5 or more; still even more preferably the process for        suppressing the foaming, wherein the compound is a compound of        formula (I) or a pharmaceutically acceptable salt thereof, or a        solvate of them.

In a preferred embodiment, the invention provides the pharmaceuticalformulation according to the first aspect, which comprises a 0.5 to 20mg part of the basic agent relative to a 100 mg part of the effectiveingredient. More preferably, the invention provides the pharmaceuticalformulation according to the first aspect, which may be obtained byadding a 5 to 20 mg part of the basic agent to a 100 mg part of thecompound of the formula (I) or a solvate thereof. In another preferredembodiment, the invention also provides the process for suppressing thefoaming according to the second aspect, wherein the compound is acompound of formula (I) or a pharmaceutically acceptable salt thereof,or a solvate of them, and wherein a 0.5 to 20 mg part of the basic agentis added to a 100 mg part of the compound.

The present invention is suitable for an effective ingredient with adissociation constant (pKa value) of 8 or more. Dissociation constant ofeffective ingredients may be determined by well-known methods such aspotentiometric titration. It is preferred that the invention is appliedto effective ingredients with a dissociation constant of 8 to 10, morepreferably 8.5 to 9.5. The invention is not practically suitable foreffective ingredients with a very high pKa value, since it is necessaryto elevate the pH sufficiently to dissociate a phenolic hydroxyl group,which requires an additional step for pH rearrangement beforeadministration. On the other hand, when effective ingredients with avery low pKa value are dissolved or suspended, then no foaming occurs,in which the invention is not necessary.

As used herein, “surface tension as determined by Wilhelmy method” meansa surface tension obtained by dissolving or suspending an effectiveingredient solely in a water to provide a solution or a suspension at aconcentration of 30 to 40 mM, and determining the solution or thesuspension for surface tension at 25° C. by Wilhelmy method. Effectiveingredients that lead to a surface tension of 60 mN/m or less,preferably 50 to 60 mN/m as determined by Wilhelmy method may be appliedto the present invention. Effective ingredients that lead to a highsurface tension hardly induce relatively the foaming, creating noproblem, whereas effective ingredients that lead to a low surfacetension are more likely to induce the foaming, which induction of thefoaming might not be suppressed by the present invention practically.

Wilhelmy method is well-known as a method for determining surfacetensions (Bussei Butsuri Kagaku (Nankodo), K122 Determination of SurfaceTension, CMC and Synergic Effects Users Manual (Kruess)). According tothe method, a clean glass or thin metal plate is hung vertically and theend of the plate is submerged into a liquid, followed by determining theforce that the plate is drawn downward.

As used herein, preferred effective ingredients are a compound offormula (I) or a pharmaceutically acceptable salt thereof, or a solvateof them.

In the formula, a metabolizable ester residue means any ester residuethat is subjected to chemical or metabolic decomposition to provide apharmacologically active compound in living bodies. Preferred esterresidues include simple aliphatic or aromatic esters derived from theacidic groups of the original compounds. More preferred ester residuesare C1-C6 alkyl esters of the acidic groups (for example, methyl esters,and ethyl esters). If necessary, double-ester type prodrugs may beprepared such as (acyloxy)alkyl ester, and ((alkoxycarbony)oxy)alkylester.

“C1-C6 Alkylene” means a straight or branched alkylene group having oneto six carbon atoms, and includes, for example, methylene, ethylene,trimethylene, tetramethylene, and hexamethylene.

“C2-C6 Alkenylene” means a straight or branched alkenylene group havingtwo to six carbon atoms, and preferred examples thereof are a group of—(CH═CH)m— wherein m is an integer of 1 to 3.

“C1-C6 Alkyl” means a straight or branched alkyl group having one to sixcarbon atoms, and includes, for example, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl,neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, andt-hexyl.

“Pharmaceutically acceptable salts” of a compound of the effectiveingredient are salts obtained by the reaction with a suitable organic orinorganic acid, or a suitable organic or inorganic base. Salts formedwith inorganic acids include salts with hydrochloric acid, hydrofluoricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,perchloric acid, hydriodic acid, and the like. Salts formed with organicacids include salts with formic acid, acetic acid, trifluoroacetic acid,fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid,succinic acid, malic acid, mandelic acid, ascorbic acid, lactic acid,and the like. Examples of organic bases include triethylamine andpyridine. Examples of inorganic cases include alkaline metals such assodium and potassium, and alkaline-earth metals such as calcium andmagnesium. Solvates include those formed with organic solvents and/orwater, and may be coordinated with any number of solvent molecule forone molecule of a compound of effective ingredient.

As used herein, basic agents are not limited to specific species as longas they render the pH of a solution or a suspension containing aneffective ingredient 8.5 or more. Specific examples include sodiumhydroxide, potassium hydroxide, and calcium hydroxide. Amounts of basicagents are preferably 0.5 to 20 mg for 100 mg of effective ingredient.The pH of a solution or a suspension of an effective ingredientcomprising a basic agent is 8.5 or more, preferably 9 to 9.8.

Amounts of basic agents “comprised” in a pharmaceutical formulation ofthe present invention are denoted as the amount of basic agents that isadded relatively to 100 mg of effective ingredient, and the denotationare not affected by the subsequent changes in the amounts due to theformation of salts with phenolic hydroxyl groups.

“Solution or suspension” includes a state or a condition in which aneffective ingredient has been dissolved or suspended in a suitableaqueous solvent. Preferably 10 to 500 mg, more preferably 100 to 400 mg,still more preferably 250 to 350 mg of a effective ingredient isdissolved or suspended in 1 to 500 ml, preferably 1 to 50 ml, morepreferably 5 to 20 ml of an aqueous solvent to provide a solution or asuspension. Aqueous solvents are preferably water for injection,infusion liquids such as physiological saline, amino acids-containinginfusion, and buffers such as phosphate buffers, and more preferredexamples include water for injection or infusion liquids having pH 5 to6.

For example, in case that an effective ingredient is a compound offormula (I) or a pharmaceutically acceptable salt thereof, or a solvateof them, a solution or a suspension having pH 8.5 or more is obtained byone of the following processes;

-   (A) A 0.5 to 5 mg part, preferably a 1 to 3 mg part, more preferably    a 1.5 to 2.5 mg part of a basic agent is added to a 100 mg part of a    compound (I) or a pharmaceutically acceptable salt thereof, or a    solvate of them, preferably compound 1; and-   (B) A 5 to 20 mg part, preferably a 10 to 20 mg part, more    preferably a 12 to 18 mg part of a basic agent is added to a 100 mg    part of a compound (I) or a solvate thereof, preferably a free acid    wherein the two COONa groups on compound 1 are both COOH groups    (compound 2). Both pharmaceutical formulations as prepared according    to processes (A) and (B) are fallen within “pharmaceutical    formulations which comprise a 0.5 to 20 mg part of a basic agent    relative to a 100 mg part of an effective ingredient”.

As described above, the same pharmaceutical formulations can be preparedby various processes including not only a process which comprises addinga basic agent to a compound as an intended effective ingredient, butalso processes which comprise adding different salt forms of compoundsincluding also free compounds such as free acids with a basic agent inamounts according to the salt forms.

In case of the administration via intravenous infusion, an effectiveingredient may be administered after preparing it to a solution or asuspension in vials, and then transferring it to infusion solution bags,and, in this case, even if the pH in the infusion solution bags is made8.5 or less, that causes no problem since the object of the presentinvention has been achieved.

In the present invention, pharmaceutical formulations can be any dosageform as long as a solution or a suspension gives a pH of 8.5 or more. Inother words, the pharmaceutical formulations of the present inventioninclude solutions, suspensions, and lyophilized formulations includingkit formulations for infusion such as double bag type kit formulations.

The present invention also provides pharmaceutical formulations whichfurther comprises a saccharide such as glucose, maltose, lactose,sucrose, fructose and mannitol (preferably mannitol), or an amino acid,preferably a neutral amino acid, preferably glycine, alanine (morepreferably alanine). It is preferred that the content of saccharide is25% (w/w) or more relative to the effective ingredient, more preferably40% to 60% (w/w), even more preferably 50% (w/w). This suppresses thedecomposition of an effective ingredient. There is no upper limit inamounts of a saccharide or an amino acid to suppress the decompositionof an effective ingredient, although an excessive amount of a saccharideor an amino acid may react with an effective ingredient to produce newside-products.

A process for suppressing the foaming according to the present inventioncan be utilized in any case in which the foaming is disadvantageous suchas the pharmaceutical field, as well as food and chemical fields. Inother words, the present invention can be utilized in any case in whichthe foaming that occurs when a compound is dissolved or suspended in anaqueous solvent should be suppressed, which compound 1) has a phenolichydroxyl group, 2) shows a dissociation constant (pKa value) of 8 ormore, and 3) causes a surface tension of 60 mN/m or less as determinedby Wilhelmy method (solvent: water, determination temperature: 25° C.)when dissolved or suspended at a concentration of 30 to 40 mM.

Aqueous solvents as used herein typically include water, infusionliquids such as a physiological saline, and an amino acids-containinginfusion, buffers, water for injection, and preferably water forinjection and infusion liquids.

According to the present embodiment, the present invention provides aprocess for suppressing the foaming that occurs at storage, whichcomprises dissociating the phenolic hydroxyl group. Preferred method fordissociations include the use of basic agents, more preferably sodiumhydroxide, potassium hydroxide, and calcium hydroxide.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing the relationship between the concentration andthe surface tension of compound 1 at pH 7 to 7.5, and pH9.5.

FIG. 2 is a graph showing the relationship between the amount of thefoaming and pH as determined by Ross-Miles Foaming Test.

BEST MODE FOR CARRYING OUT THE INVENTION

1) Wilhelmy Method

Ingredient for which the present invention is suitable can be selectedby Wilhelmy method as described below.

Preparation of Samples to be Tested

A compound to be determined that has been weighed is dissolved orsuspended in a defined amount of a distilled water. As such, samples ofaqueous solutions to be tested containing the compound at variousconcentrations are prepared, and each of the solutions is adjusted to be50 ml aliquots.

Setup of Determination Device

Surface tension-measuring device (Kruess Inc., Type K12) and thepersonal computer for control and analysis are started, and a softwarefor determining surface tension (Kruess Inc., K122) is launched. Thedetermination site of the device is subjected to the circulation of thewater from a thermostatic chamber to keep the temperature constant at25° C. The glass vessel (diameter: 65 mm, height: 40 mm) into which asample to be tested is placed is washed thoroughly with water, andfinally washed with acetone, thus being dried for use.

Setup of Plate for Determination

Plate as used for the determination is usually made of platinum, andassumes a rectangular shape of 19 mm in width, 10 mm in height, and 0.2mm in thickness. The plate is burnt over a gas burner in order to removeresidual materials attached to the surface before the start of thedetermination. On each determination of the sample to be tested, plateis washed with a distilled water and acetone, and dried.

Blank Determination

Forty ml of a distilled water is poured into the vessel that have beenwashed, and the vessel is placed into the surface tension-measuringdevice. Using the automatic detection function of the device, the end ofthe plate is submerged into the water up to 2 mm in depth from thesurface of the water. In this condition, surface tensions aredetermined. Graphs of surface tensions versus time is displayed on thePC. When the value of surface tension as determined one minute later isalmost constant, then the value is recorded and the determination isstopped.

Sample Determination

After the blank determination, 40 ml of a sample of aqueous solutions ispoured into the vessel that have been washed, and the vessel is placedinto the surface tension-measuring device. Using the automatic detectionfunction of the device, the end of the plate is submerged into thesample up to 2 mm in depth from the surface of the sample. In thiscondition, surface tensions are determined. Graphs of surface tensionsversus time is displayed on the PC. When the value of surface tension asdetermined one minute later is almost constant, then the value isrecorded and the determination is stopped. When the value changes and isnot constant, then the determination is continued until the value isconstant, which constant value is in turn recorded.

2) Pharmaceutical Formulations

Pharmaceutical formulations of the present invention may be prepared byconventional methods according to dosage forms. In case of thepreparation of injectable formulations, the following process may beadapted.

Instruments and materials as used in the preparation are preliminarilysterilized by conventional methods such as autoclaving, dry heatsterilization, and gamma ray-sterilization, in light of the form, theheat resistance, and the pressure tightness of the subject to besterilized.

An effective ingredient and a saccharide if necessary that have beenweighed are placed into a container for injection, and an appropriateamount of a solvent such as water for injection is added thereto, afterwhich the mixture is stirred to prepare a solution or a suspension. Theconcentration of the effective ingredient in the solution or thesuspension may be defined in light of the kinds of the solvent,solubility of the effective ingredient to the solvent, and theconcentration at the time of reconstitution. Further, a basic agent isadded for example in a form of 0.1 to 10 mol/L, preferably 1 mol/Laqueous solution so as to adjust the pH to 8.5 or more.

The solution or suspension thus obtained is sterilized by filtrationaccording to conventional methods. If necessary, rough filtration may beconducted to remove the decomposed materials and contaminants before thesterilization by filtration.

The liquid sterilized by filtration is portioned into vials asappropriate, and lyophilized to give intended injectable formulation.

EXAMPLES

The following examples and test examples are presented for purpose offurther illustration of the invention, and such examples are notintended to be limiting the invention in any respect.

Test Example 1

Determination of Surface Tension of Compound 1

The inventors assumed the foaming in compound 1 be caused predominantlyby the surface activity of compound 1, and therefore the surface tensionof the aqueous solution of compound 1 was determined by Wilhelmy method(Hanging plate method) (Bussei Butsuri Kagaku (Nankodo), K122Determination of Surface Tension, CMC and Synergic Effects Users Manual(Kruess)).

Compound 1 was dissolved in a distilled water to prepare each 50 ml ofaqueous solutions containing compound 1 in various concentrations.

Surface tension-measuring device (Kruess Inc., Type K12) and thepersonal computer for control and analysis ware started, and a softwarefor determining surface tension (Kruess Inc., K122) was launched. Thedetermination site of the device was subjected to the circulation of thewater from a thermostatic chamber to keep the temperature constant at25° C. The glass vessel (diameter: 65 mm, height: 40 mm) into which asample to be tested was placed was washed thoroughly with water, andfinally washed with acetone, thus being dried for use.

The plate that was made of platinum, and assumed a rectangular shape of19 mm in width, 10 mm in height, and 0.2 mm in thickness was used forthe determination. The plate was burnt over a gas burner in order toremove residual materials attached to the surface before the start ofthe determination. On each determination of the sample to be tested,plates were washed with a distilled water and acetone, and dried.

At first, blank determination was conducted. Forty ml of a distilledwater was poured into the vessel that had been washed, and the vesselwas placed into the surface tension-measuring device. Using theautomatic detection function of the device, the end of the plate wassubmerged into the water up to 2 mm in depth from the surface of thewater. In this condition, surface tensions were determined. Graphs ofsurface tensions versus time was displayed on the PC. The value ofsurface tension as determined one minute later was almost constant, andtherefore the value was recorded and the determination was stopped. Thedetermination was repeated twice, and the average was estimated.

Subsequently, sample determination was conducted. Forty ml of eachsample of the aqueous solutions containing compound 1 in variousconcentrations (aqueous solution of compound 1, pH7 to 7.5) was pouredinto the vessel that had been washed, and the vessel was placed into thesurface tension-measuring device. Using the automatic detection functionof the device, the end of the plate was submerged into the sample up to2 mm in depth from the surface of the sample. In this condition, surfacetensions were determined. Graphs of surface tensions versus time wasdisplayed on the PC. When the value of surface tension as determined oneminute later was almost constant, then the value was recorded and thedetermination was stopped. When the value changes and was not constant,then the determination was continued until the value was constant (over1 to 2 minutes), which constant value was in turn recorded. Thedetermination was repeated twice, and the average was estimated.

Average values of surface tension (n=2) obtained as the results wereplotted against each of logarithmic concentrations.

Further, aqueous solution containing compound 1 at variousconcentrations, which were adjusted to pH 9.5 with sodium hydroxide weredetermined for surface tension. The relationship between the surfacetension at pH7 to 7.5 and pH9.5, and the concentrations of compound 1 isshown in FIG. 1.

The results of the determination of surface tension showed that thedecrease in the surface tension is inhibited at pH 9.5 more than that atpH7 to 7.5.

The value of surface tension in the 37.6 mM solution of compound 1 at25° C. was 53.9±0.2 mN/m.

Example 1

Fifteen hundreds g of a water for injection was added to 100.7 g of thebulk of compound 1 (90.0 g of the net content of compound 1) as preparedaccording to the process described in Japanese Patent Publication(kokai) No. 53484/1995 and 45.0 g of D-mannitol, and those solutes weredissolved, after which the solution was thoroughly stirred until turningtransparently pale yellow. After the dissolution, the pH of the solutionwas determined while 1 mol/L aqueous sodium hydroxide was added drop bydrop. At the time when the pH of the solution reached 9.5, the additionof aqueous sodium hydroxide was stopped (total added amount of theaqueous solution was 55 g), and an additional water for injection wasadded thereto until the total weight of the solution was 1800.0 g. Thepreparation liquid was roughly filtered through 0.45 μm filters, andthen filtered through 0.22 μm filters to be sterilized. The sterilizedfiltrate was portioned into vials at 6.0 g (within ±1%) per vial, andlyophilized. The lyophilization of the filtrates was conducted bypreliminarily freezing at −40° C., then primarily drying at −5° C. at 10Pa for 24 hours or more, and secondarily drying at 60° C. at 2Pa for 5hours. After the completion of the lyophilization, the vials were woundup with caps to prepare injectable formulations.

Example 2

To 3.81 g of compound 2 (4.00 g of the net content of compound 1), 2.00g of d-mannitol and 64 g of 0.16 mol/L aqueous sodium hydroxide wereadded, and those solutes were dissolved. To the solution, 1 mol/Laqueous sodium hydroxide was added to adjust the pH 9.5 (total addedamount of the aqueous solution was 4.79 g). An additional water forinjection was added thereto until the total weight of the solution was80.0 g, and the concentration was adjusted 50.0 mg/g. The preparationliquid was sterilized by filtration, and was portioned into vials at2.00 g per vial, followed by being lyophilized. The lyophilizedformulations comprise 100 mg of compound 1 (as 2 Na salt).

Test Example 2

Comparison in Foaming

Ten ml of a water for injection was added to the formulation as preparedin Example 1 or 2, and the mixture was shaken to facilitate thedissolution, during which the foaming was observed. Additionally, 100 mgof compound was dissolved in 10 ml of a water for injection to preparethe comparative formulation (pH 7.5), and the foaming was observed forcomparison. The results are shown in the following table.

TABLE 1 Formulation of Example 1 formulation or 2 Comparativeformulation Foaming The shaking caused a small The shaking caused theamount of foaming, which foaming that spread inside disappeared withinone the whole vials, which did minute. not disappear even after left for24 hours.

Test Example 3

Foaming of the Formulation Having a High pH Without Mannitol

To the formulation as prepared according to Example 1 except that nomannitol was added, 10 ml of a water for injection was added, and themixture was shaken to dissolve the solutes, during which the foaming wasobserved. The shaking caused a small amount of foaming, but the foamingdisappeared within one minute. The degree of foaming was similar to theformulation of Example 1 that was added with mannitol.

Test Example 4

Relationship Between Foaming and pH

Compound 1 was dissolved in a water for injection (0.1% w/w), and thesolution was quantitatively determined for foaming by Ross-Miles FoamingTest. Ross-Miles Foaming Test was conducted according to the method asdefined in International Standard ISO 696-1975 except that thedetermination temperature was set 25° C. The relationship between thefoaming occurred in the present test and the pH is shown in Table 2.This shows that the foaming was inhibited depending on the increase inpH.

Example 3

Effect of Mannitol on Inhibition of Decomposed Materials Production

After the formulation as prepared according to Example 1 was stored at50° C. for 2 months, the amounts of decomposed materials produced byhydrolysis were determined and compared. Typical decomposed materialsare:

The relationship of the contents of compound 1, the amounts of thedecomposed materials, and the added amounts of D-mannitol comprised inbetween the formulation before the storage and that after the storage at50° C. for 2 months, is shown in Table 2. The determination wasconducted using high performance liquid chromatography (HPLC). Thedetermination conditions of HPLC are as shown below:

-   Device: Waters 600E,484,712 wisp,74 1,FD20A-   Column: J'sphere ODS-L80, S-4μm, 80A 150×4.6 mmφ-   Moving phase: water/acetonitrile/acetic acid=100/100/1-   Flow rate: 1.0 ml/min-   Injected volume:    -   20 μL (at the time for determination of impure materials)    -   10 μL (at the time for determination of compound 1)-   Detection wavelength    -   275 nm-   Detection sensibility (AUFS):    -   0.64 (at the time for determination of impure materials)    -   0.20 (at the time for determination of compound 1)-   Solvent for dilution of samples:    -   water/acetonitrile/acetic acid=100/100/1-   Concentration of samples    -   1 mg/ml (at the time for determination of impure materials)    -   60.0 μg/ml (at the time for determination of compound 1)

TABLE 2 Effect of mannitol on the content of compound 1 and the amountof decomposed materials (%) 1 Added amount of D-mannitol (% of theweight of compound 1) 0% 25% 50% 100% Content of compound 1 97.1 ± 0.1 97.9 ± 0.4  98.0 ± 0.1  98.3 ± 0.1  (after storage at 50° C. for 2months) compound A Before storage 0.26 ± 0.02 0.13 ± 0.01 0.11 ± 0.010.11 ± 0.01 After 1.71 ± 0.08 0.44 ± 0.01 0.24 ± 0.01 0.23 ± 0.02storage at 50° C. for 2 months Other Before 0.32 ± 0.02 0.33 ± 0.03 0.32± 0.02 0.31 ± 0.01 related storage compounds After 0.66 ± 0.14 0.87 ±0.02 0.89 ± 0.05 1.24 ± 0.05 storage at 50° C. for 2 months

Table 2 shows that the addition of D-mannitol suppressed the productionof a decomposed product, compound A. Also, this suggested that thedecrease in the content of compound 1 was suppressed.

INDUSTRIAL APPLICABILITY

A process for suppressing the foaming according to the present inventioncan be utilized at the time of the preparation of solutions orsuspensions of foods and pharmaceuticals, and is useful for convenientpreparation or manufacture of food products, and for accurateadministration of pharmaceutical products.

1. An injectable pharmaceutical formulation which comprises the compoundof formula (I):

or a pharmaceutically acceptable salt thereof, mannitol and a basicagent, wherein the basic agent is sodium hydroxide, and wherein the pHof the formulation in a state of solution or suspension is 8.5 to 9.8,and wherein foaming is suppressed.
 2. The pharmaceutical formulationaccording to claim 1, wherein the formulation is lyophilized.
 3. Thepharmaceutical formulation according to claim 1, which is prepared bydissolving or suspending the pharmaceutical formulation in water forinjection or an infusion, wherein in the formulation is lyophilized. 4.The pharmaceutical formulation according to claim 3, wherein theformulation is dissolved or suspended in 5 to 20 ml of water forinjection or an infusion liquid.
 5. The pharmaceutical formulationaccording to claim 1, wherein the pH of the formulation in a state ofsolution or suspension is 9 to 9.8.
 6. The pharmaceutical formulationaccording to claim 1, wherein the content of the mannitol is 25% (w/w)or more relative to the compound of formula (I).
 7. The pharmaceuticalformulation according to claim 6, wherein the content of the mannitol is40% to 60% (w/w) relative to the compound of formula (I).
 8. Thepharmaceutical formulation according to claim 1, wherein decompositionof the compound of formula (I) is suppressed.
 9. A process forsuppressing the foaming of an injectable pharmaceutical formulationwhich comprises the compound of formula (I):

or a pharmaceutically acceptable salt thereof, mannitol and a basicagent, wherein the basic agent is sodium hydroxide, and wherein the pHof the formulation in a state of solution or suspension is adjusted to8.5 to 9.8.
 10. The pharmaceutical formulation according to claim 1,comprising: (A) 0.5 to 20 mg part of the basic agent relative to 100 mgpart of a disodium salt of the compound of formula (I); or (B) 12 to 18mg part of the basic agent relative to 100 mg part of the compound ofthe formula (I).